bims-mihora 2026-06-28 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2026–06–28
fifteen papers selected by
Lisa Patel, Istesso

The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.
FUBL-3/FUBP1 mediates mitochondrial stress-induced chromatin remodeling and longevity.
Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.
Dysregulation of the HSF1-Mediated UPRmt Pathway in Colonic Smooth Muscle Cells Drives Motility Dysfunction in Functional Constipation.
The therapeutic effect of nicotinamide riboside chloride on ameliorating alcohol-induced neuronal damage with a focus on mitochondrial unfolded protein response and mitophagy.
Sensory decline in aging and neurodegeneration: A mitochondrial perspective.
Mitochondrial stress response drives microglial senescence.
Immune metabolic remodeling during exercise rehabilitation: Linking skeletal muscle regeneration, bone homeostasis, and systemic immune adaptation.
Tuning the Fire: Context-Dependent Mitochondrial ROS Signaling, Mitohormesis, and Redox-Modulating Interventions.
[Progress on mechanism of mitochondrial autophagy in pathogenesis of intervertebral disc degeneration based on PINK1/Parkin signaling pathway].
Revitalizing Muscle Repair: Hyaluronan Preserves Mitochondrial Architecture and Promotes Myogenesis Under Pro-Inflammatory Conditions.
Mammalian Respiratory Chain Complex Assemblies and Their Links to Mitochondria Stress-Induced Human Diseases.
UHPLC-MS based metabolomics study of the ErZhi formula on skeletal muscle against osteosarcopenia focusing on energy metabolism.
Photobiomodulation Targets Mitochondrial Homeostasis for Diabetic Wound Healing.
Mitochondria: The Crossroads of Complement Activation and Kidney Injury Progression.

Nat Neurosci. 2026 Jun 26.

The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.

Maria Jose Perez J, Alicia Lam, Christin Weissleder, Federico Bertoli, Hariam Raji, Mariella Bosch, Ivan Nemazanyy, Stefanie Kalb, Mohammed Kehili, Insa Hirschberg, Dario Brunetti, Indra Heckenbach, Morten Scheibye-Knudsen, Michela Deleidi.

Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPRmt) to maintain proteostasis and promote recovery under stress. Studies in simple organisms have shown that UPRmt activation in glial cells supports proteostasis through beneficial non-cell-autonomous communication with neurons. However, the role of mitochondrial stress responses in the human brain remains unclear. To address this gap, we investigated the cell-type-specific effects of mitochondrial proteotoxic stress using human induced pluripotent stem cell-derived neuronal and glial cultures, as well as brain organoids. Here we show that mitochondrial proteotoxic stress induces metabolic rewiring in human microglia, marked by depletion of S-adenosylmethionine and lipid remodeling, ultimately leading to a senescent phenotype. Using human neuronal-glial tricultures and microglia-containing brain organoids, we identified the specific contributions of microglia to brain senescence and mitochondrial stress-driven neurodegenerative processes. UPRmt activation disrupts microglial communication with neighboring cells, triggering inflammatory signaling and impairing proteostasis. Together, these findings reveal how impaired mitochondrial proteostasis alters intercellular networks and identify a critical role for the UPRmt in neurodegenerative disease pathogenesis.

DOI: https://doi.org/10.1038/s41593-026-02320-1
Sci Adv. 2026 Jun 26. 12(26): eaec8143

FUBL-3/FUBP1 mediates mitochondrial stress-induced chromatin remodeling and longevity.

Qian Zhang, Hangyu Dong, Yayun Jiang, Zihao Wang, Jiasheng Li, Ye Tian.

Mitochondrial stress activates nuclear transcriptional programs to restore homeostasis and promote longevity; yet, the nuclear effector that directly reshapes chromatin during stress remains unclear. Through a forward genetic screen in Caenorhabditis elegans, we identify FUBL-3, the homolog of human far-upstream elements binding protein 1 (FUBP1), as a conserved regulator that couples mitochondrial stress to chromatin remodeling. FUBL-3 translocates to intestinal nuclei upon stress, where it drives nucleosome remodeling and deacetylase-dependent chromatin condensation and activates mitochondrial unfolded protein response (UPRmt). Loss of fubl-3 disrupts chromatin compaction and abolishes stress-induced lifespan extension, while its overexpression is sufficient to restructure chromatin, trigger UPRmt, and extend lifespan. Notably, human FUBP1 rescues fubl-3 mutants in worms and mediates chromatin remodeling in mammalian cells under mitochondrial stress. FUBP1 binds promoters of proteostasis and mitochondrial quality control genes, supporting its role in nuclear adaptation. Our study identifies FUBL-3/FUBP1 as a conserved mitochondrial-to-nuclear communicator that reprograms chromatin architecture to promote stress resilience and healthy aging.

DOI: https://doi.org/10.1126/sciadv.aec8143
Cell Death Dis. 2026 Jun 25.

Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.

Lauren Brakefield-Laird, Amit Budhraja, Peter M Hall, Dixie Brewington, Jamila Moore, Josi Lott, Yonghui Ni, Dennis Voronin, Oliver Grant-Chapman, Tresor O Mukiza, Tristen Wright, Yong-Dong Wang, Sandi Radko-Juettner, Shondra M Pruett-Miller, Stanley Pounds, Peter Vogel, Joseph T Opferman.

MCL-1 (myeloid cell leukemia-1) promotes survival and confers therapeutic resistance in acute myeloid leukemia (AML), particularly in high-risk subtypes harboring KMT2A rearrangements (KMT2A-r). Clinical trials involving patients with hematological malignancies treated with MCL-1 inhibitor monotherapy have been hampered by dose-limiting toxicity and poor response rates. Therefore, we sought to identify combinatorial treatment approaches to enhance the efficacy of MCL-1 inhibitors with the goal of improving response rates and limiting toxicities. Here, we report the inhibition of electron transport chain (ETC) complex I (CI) function as a synthetic lethal partner for MCL-1 inhibition. Co-targeting CI and MCL-1 synergistically reduces the viability in AML cell lines and patient-derived xenograft (PDX) samples in vitro, while significantly prolonging survival in mice bearing PDX AML, indicating the preclinical potential for this combinatorial therapy. These findings provide a mechanistic rationale and preclinical evidence for dual inhibition of MCL-1 and CI as a therapeutic strategy, offering a potential path to overcome resistance to single-agent MCL-1 inhibitors and improve outcomes for patients with high-risk AML. Mechanistically, we reveal that CI inhibition induces the activation of the integrated stress response, resulting in ATF4 activation downstream of the eIF2α kinase, HRI (Heme-regulated inhibitor). HRI activation via CI inhibition is dependent on the mitochondrial stress messenger, DELE1. Together, these results indicate that co-inhibition of MCL-1 and ETC CI function has the potential for improving responses in patients with KMT2A-r AML.

DOI: https://doi.org/10.1038/s41419-026-09037-w
Biomolecules. 2026 Jun 12. pii: 868. [Epub ahead of print]16(6):

Dysregulation of the HSF1-Mediated UPRmt Pathway in Colonic Smooth Muscle Cells Drives Motility Dysfunction in Functional Constipation.

Junpeng Yao, Wen Wang, Wei Zhang, Hang Dong, Yujun Hou, Qianhua Zheng, Ying Li, Fang Zeng.

  Mitochondrial dysfunction in colonic smooth muscle cells (SMCs) is closely associated with impaired gut motility in functional constipation (FC), but the underlying molecular mechanisms remain incompletely understood. The mitochondrial unfolded protein response (UPRmt) is a critical pathway for maintaining mitochondrial proteostasis, and heat shock factor 1 (HSF1) acts as an important upstream regulator of this response. In the present study, we employed a loperamide-induced FC mouse model, combined with single-cell transcriptomic, molecular, and functional analyses to characterize the HSF1-UPRmt pathway in colonic SMCs and to investigate its role in FC. Single-cell transcriptomic analysis of colon tissue from FC mice revealed marked downregulation of UPRmt-associated genes in colonic SMCs. Immunofluorescence, Western blotting, and RT-qPCR analyses of colonic tissue confirmed that HSF1 expression was reduced in colonic SMCs, along with the downregulation of the UPRmt components, including HSP60, mtHSP70, and LONP1. These molecular changes were accompanied by mitochondrial structural damage, seen by transmission electron microscopy, and by functional impairments, including reduced mitochondrial membrane potential, elevated mtROS production, decreased ATP levels, and diminished activities of respiratory chain complexes I-V. AAV9-mediated overexpression of HSF1 reactivated the UPRmt pathway, improved mitochondrial function, and ameliorated constipation, whereas shRNA-mediated knockdown of HSF1 further suppressed UPRmt activity and aggravated mitochondrial damage, indicating that HSF1 bidirectionally regulates this pathway. Complementary experiments in primary colonic SMCs confirmed that this regulatory mechanism operates in a cell-autonomous manner, as modulation of HSF1 expression produced corresponding changes in the UPRmt pathway, in the expression of mitochondrial respiratory chain complex subunits (ATP5A, NDUFA9, COX1, SDHA, UQCRC1), and in ATP production, mirroring the in vivo findings. Collectively, these results demonstrate that HSF1 plays a pivotal role in maintaining mitochondrial homeostasis in colonic SMCs through regulation of the UPRmt pathway and that HSF1 dysfunction is closely associated with slowed gut motility in FC. These findings offer a new mechanistic perspective on FC and point to the HSF1-UPRmt axis as a potential therapeutic target.

Keywords:  functional constipation; gut motility; heat shock factor 1; mitochondrial unfolded protein response; smooth muscle cell

DOI:  https://doi.org/10.3390/biom16060868
Genes Dis. 2026 Sep;13(5): 101886

The therapeutic effect of nicotinamide riboside chloride on ameliorating alcohol-induced neuronal damage with a focus on mitochondrial unfolded protein response and mitophagy.

Jinyang Wang, Jianan Wang, Wei Xie, Qi Shen, Chengbin Wang, Ruibing Li, Shixiong Deng.

  Excessive alcohol consumption leads to neurodegeneration, driven primarily by oxidative stress and mitochondrial dysfunction, yet no specific treatment exists. Nicotinamide riboside chloride (NRC), a nicotinamide adenine dinucleotide precursor, has demonstrated therapeutic potential in mitigating mitochondrial dysfunction in heart failure, but its role in alcohol-induced neurodegeneration remains unexplored. This study investigated NRC's neuroprotective effects using behavioral tests, serum ethanol and inflammatory marker analysis, hematoxylin-eosin staining, and molecular assays of in vitro models. Proteomics and GEO database analysis further elucidated the mechanisms of alcohol-induced brain injury. Results showed that NRC significantly improved alcohol-related cognitive impairment and neuroinflammation. Both our experimental data and external datasets identified mitochondrial dysfunction as a key driver of alcohol-induced neuronal damage, characterized by impaired mitophagy and disrupted mitochondrial unfolded protein response (UPRmt). NRC supplementation restored mitochondrial homeostasis by enhancing UPRmt and Fundc1-dependent mitophagy. Mechanistically, UPRmt inhibition abolished NRC's protective effects by suppressing Fundc1 expression and mitophagy, whereas mitophagy inhibition did not affect UPRmt, suggesting a hierarchical regulation where UPRmt governs Fundc1-mediated mitophagy. In conclusion, alcohol disrupts mitochondrial quality control, but NRC counteracts neuronal toxicity by activating UPRmt and restoring Fundc1-driven mitophagy, offering a promising therapeutic strategy for alcohol-related neuronal damage.

Keywords:  Alcohol; Mitophagy; Neuron; Nicotinamide riboside chloride; Unfolded protein response

DOI:  https://doi.org/10.1016/j.gendis.2025.101886
Pharmacol Res. 2026 Jun 25. pii: S1043-6618(26)00237-9. [Epub ahead of print]230 108322

Sensory decline in aging and neurodegeneration: A mitochondrial perspective.

Oluwamayomikun Adeboye, Bianca L Gonda, Nikita Gulati, Keming Hu, Alexa R Karp, Dylan C McNally, Wesley Tsai, Jennyfer G Zarate, Madison Holmes, Lanae Johnson-Kleinpeter, Hay Young Kwok, Victory J Miranda, Julie H Nguyen, Karishma A Patel, Apurva Polagoni, Bryan Ramirez, Renata T Da Costa, Cameron R Love, Andrey Grigoriev, Maria E Solesio.

  Sensory organs (touch, sight, hearing, smell, and taste) are the primary way humans perceive the environment. Accordingly, sensory decline deleteriously affects patients' quality of life, and it is often associated with a worse prognosis of related pathologies. This decline has been broadly described in aging and in the main aging-related neurodegenerative disorders, even though it is often understudied and considered a minor symptom. The molecular pathways that drive aging-associated sensory decline are broad and diverse; however, mitochondrial dysfunction has been described at the intersection of many of these mechanisms. Mitochondria have robust mechanisms to maintain their homeostasis. These mechanisms include, for example, the unfolded protein response, the antioxidant systems, and mitophagy. During aging, these mechanisms are dysregulated, which contributes to the dysfunction of the organelle. For example, increased reactive oxygen species generation and mitochondrial DNA mutations are present in cells and tissues, the dysregulation of which is crucial for the onset of sensory decline. In this bibliographical review, we systematically and comprehensively discuss the most significant and recent findings in the field. The studies we describe here suggest that targeting mitochondrial dysfunction could be a valid, innovative, and promising pharmacological target against sensory decline in aging and aging-related neurodegenerative disorders. Moreover, targeting mitochondrial dysfunction might have positive effects on other symptoms of aging and associated pathologies, including Parkinson's and Alzheimer's Diseases. Further research in the field could significantly contribute to decreasing sensory decline, which could positively impact both lifespan and healthspan.

Keywords:  Mitochondria; Mitochondrial dysfunction; Neurodegeneration; Sensory decline

DOI:  https://doi.org/10.1016/j.phrs.2026.108322
Nat Neurosci. 2026 Jun 26.

Mitochondrial stress response drives microglial senescence.

Luca Peruzzotti-Jametti, Stefano Pluchino.

DOI: https://doi.org/10.1038/s41593-026-02264-6
Tissue Cell. 2026 Jun 13. pii: S0040-8166(26)00381-2. [Epub ahead of print]103 103687

Immune metabolic remodeling during exercise rehabilitation: Linking skeletal muscle regeneration, bone homeostasis, and systemic immune adaptation.

Fei Wang, Wenjie Qin.

  Exercise rehabilitation harnesses immune metabolic remodeling to drive coordinated skeletal muscle regeneration, bone homeostasis, and systemic immune adaptation. Physical activity functions as a controlled metabolic stressor that reprograms immune cell metabolism-shifting macrophages from glycolytic M1 to oxidative M2 phenotypes, expanding regulatory T cells through fatty acid oxidation and ketone body signaling, and modulating neutrophils, NK cells, and B cells via lactate, succinate, itaconate, ROS, NAD⁺, and gut-derived SCFAs. These metabolic shifts regulate immune cell polarization, efferocytosis, cytokine profiles, and growth factor release (IGF-1, amphiregulin, GDF-15), creating an optimal regenerative niche for satellite cell activation, proliferation, and differentiation in muscle while supporting bone remodeling through mechanosensory osteocyte signaling and osteokine secretion (osteocalcin, sclerostin, RANKL/OPG). Distinct exercise modalities generate characteristic immune-metabolic signatures: aerobic training promotes sustained oxidative phosphorylation and anti-inflammatory tolerance beneficial for both muscle and bone; resistance training induces controlled glycolytic bursts followed by anabolic M2 polarization, muscle hypertrophy, and improved bone microarchitecture; HIIT generates oscillatory stress that trains innate immune memory and enhances muscle-bone resilience. Energy-sensing pathways (AMPK, mTOR, HIF-1α, SIRT1/3, PGC-1α) and metabolite checkpoints integrate mechanical loading with immune and endocrine signals to balance pro-regenerative inflammation with timely resolution across the musculoskeletal system. Clinically, this framework enables precision rehabilitation protocols based on immune metabolic phenotyping, lactate kinetics, and skeletal imaging (BMD, microarchitecture) to optimize outcomes in sarcopenia, osteosarcopenia, postoperative recovery, chronic inflammatory diseases, cancer cachexia, and post-viral syndromes. Exercise-induced immune metabolic remodeling thus serves as a master regulator of muscle-bone-immune coupling, offering a mechanism-driven foundation for next-generation rehabilitation medicine that enhances tissue repair, bone quality, and systemic homeostasis.

Keywords:  Exercise rehabilitation; Immune metabolic remodeling; Macrophage polarization; Muscle–bone crosstalk; Osteokines; Satellite cells

DOI:  https://doi.org/10.1016/j.tice.2026.103687
Biomolecules. 2026 Jun 12. pii: 867. [Epub ahead of print]16(6):

Tuning the Fire: Context-Dependent Mitochondrial ROS Signaling, Mitohormesis, and Redox-Modulating Interventions.

Evelina Charidemou, Eleni Andreou, Christos Papaneophytou.

  Mitochondrial reactive oxygen species (mtROS) are central regulators of cellular function, yet their biological roles are often reduced to an oxidative-stress/antioxidant dichotomy. This review reframes mtROS through the concept of mitohormesis, in which outcomes are neither inherently harmful nor beneficial but are determined by a defined set of contextual variables. We present a mechanistic framework in which mtROS effects depend on chemical species identity, sub-mitochondrial site of production, temporal dynamics, redox-buffering capacity, and metabolic state; together, these variables determine whether mtROS promote adaptive eustress or pathological distress. We then show that, across polyphenols, isothiocyanates, terpenoids, alkaloids, and quinones, the biologically relevant effects of natural redox-modulating compounds are mediated less by direct radical scavenging than by pro-hormetic mechanisms, including mild electron transport chain perturbation, nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (NRF2/KEAP1) activation, modulation of mitochondrial membrane potential, mitochondrial quality control, and NAD+/NADPH regulation. Applying this framework to disease reveals strong tissue and state dependence: neurodegeneration favors buffering expansion and mitophagy; metabolic disease may benefit from exercise-mimetic and NRF2-activating strategies; cardiovascular disease illustrates mitohormesis through ischemic preconditioning and CoQ10 supplementation; and cancer requires distinction between prevention and therapy because redox buffering can either protect normal tissue or support tumor survival. Finally, we argue that the failure of non-specific antioxidant supplementation is mechanistically predictable and propose context-aware, biomarker-guided, temporally optimized, and compartment-targeted redox interventions as a more rational translational path.

Keywords:  NRF2/KEAP1 pathway; mitochondria-targeted therapeutics; mitochondrial ROS; mitohormesis; phytochemicals; redox buffering; redox signaling; reverse electron transport

DOI:  https://doi.org/10.3390/biom16060867
Zhongguo Gu Shang. 2026 Jun 25. 39(6): 642-8

[Progress on mechanism of mitochondrial autophagy in pathogenesis of intervertebral disc degeneration based on PINK1/Parkin signaling pathway].

Jie Guo, Ling Lei, Hongjing Tian, Tiefeng Guo, Linzhao Luo, Yanjun Zhang.

  Intervertebral disc degeneration (IVDD) is one of the main causes of lower back pain. The chronic accumulation of aging and apoptosis of nucleus pulposus cells (NPCs) is believed to be related to IVDD. In recent years, mitochondrial autophagy which as an important clearance mechanism within cells, has gradually attracted attention. The PINK1/Parkin signaling pathway is regarded as the key pathway regulating mitochondrial autophagy, and it plays a significant role in physiological and pathological processes of NPCs. The mechanism by which PINK1/Parkin signaling pathway mediates mitochondrial autophagy could be understood as follows, PINK1, as the sensor for mitochondrial quality regulation, is activated. It recruits and activates Parkin to the mitochondrial membrane through phosphorylation of ubiquitin, and then undergoes Parkin-dependent substrate ubiquitination, recruitment of autophagy receptors, formation of autophagosomes, and fusion with lysosomes, ultimately completing the extremely important autophagy process. Current research indicates that abnormality of PINK1/Parkin signaling pathway may be closely related to IVDD, but the specific mechanism still requires further exploration. The paper explores research progress of mechanism by which mitochondrial autophagy affects IVDD based on PINK1/Parkin signaling pathway, with the aim of providing new strategies and targets for the treatment of IVDD.

Keywords:  Intervertebral disc degeneration; Mitophagy; Nucleus pulposus cells; PINK1/Parkin signaling pathway; Review

DOI:  https://doi.org/10.12200/j.issn.1003-0034.20241146
Biomolecules. 2026 Jun 19. pii: 913. [Epub ahead of print]16(6):

Revitalizing Muscle Repair: Hyaluronan Preserves Mitochondrial Architecture and Promotes Myogenesis Under Pro-Inflammatory Conditions.

Fabio Ferrini, Giosuè Annibalini, Michela Battistelli, SeyedehMahboobeh Moosavi, Osman Riham, Fabiana Fanelli, Italo Capparucci, Piero Sestili, Elena Barbieri.

  Hyaluronic acid (HA), a major component of the glycome and a non-sulfated glycosaminoglycan, plays a crucial role in regulating stem cell behavior and function, thereby supporting skeletal muscle repair under inflammatory conditions. In this study, we investigated the effects of a mixture of HA fractions with different molecular weights (M-HA; 2-1000 kDa) on the repair capacity and myogenic potential of C2C12 murine myoblasts exposed to inflammatory stimuli. C2C12 cells were cultured, induced to differentiate, and treated with M-HA (1 mg/mL) under either physiological or inflammatory conditions (LPS, 10 µg/mL; IL-1β, 20 ng/mL). M-HA exhibited no cytotoxic effects, even at the highest concentration tested (1.0 mg/mL), and significantly enhanced scratch wound closure. Moreover, M-HA improved the myogenic index at day 5 of differentiation, promoted the expression of myogenic markers, preserved myosin heavy chain (MHC) levels under inflammatory stress, and reduced the expression of autophagy-related genes. Ultrastructural analyses revealed that untreated myotubes displayed swollen mitochondria, disrupted cristae architecture, and numerous autophagic vacuoles, whereas M-HA-treated cells exhibited well-preserved mitochondrial morphology, intact cristae organization, reduced cytoplasmic damage, and maintained myofibrillar structure. Taken together, the functional, molecular, and ultrastructural findings demonstrate that M-HA protects myoblasts from inflammation-induced cellular damage and supports their regenerative capacity. These results underscore the potential of glycomics-based strategies to enhance myogenic differentiation and promote skeletal muscle regeneration in inflammatory microenvironments.

Keywords:  C2C12; autophagy; hyaluronic acid; inflammation; myogenic differentiation

DOI:  https://doi.org/10.3390/biom16060913
Adv Exp Med Biol. 2026 ;1514 299-330

Mammalian Respiratory Chain Complex Assemblies and Their Links to Mitochondria Stress-Induced Human Diseases.

Runyu Guo, Maojun Yang.

  Mitochondria are considered the central organelle in cellular energy metabolism and an integral platform for signal transduction. Respiratory chain complexes are the most abundant and critical protein machines in mitochondria. Thanks to advancing technologies such as cryo-EM, molecular dynamics simulation, and FRET-based live imaging, though still under hot debate, we have now gained a much deeper insight into the organization, regulation, and functional mechanism of the respiratory chain. Accordingly, developing novel compounds targeting mitochondria is particularly appealing, for mitochondria dysfunction might be the underlying cause of many annoying human diseases, including metabolic syndromes, neurodegenerative diseases, cardiovascular diseases, and tumors.

Keywords:  Complex I; Drug discovery; Electron transport chain; Mitochondria; Mitochondrial disorders; Respiratory chain complexes; Signaling; Structural biology; Supercomplexes

DOI:  https://doi.org/10.1007/978-3-032-26629-3_11
Animal Model Exp Med. 2026 Jun 24.

UHPLC-MS based metabolomics study of the ErZhi formula on skeletal muscle against osteosarcopenia focusing on energy metabolism.

Yuqing Pang, Ningning Li, Yujie Ding, Shuzhen Hou, Jing Liu, Xiuxue Liu, Erwei Liu, Xiaopeng Chen.

   BACKGROUND: The ErZhi formula (EZF) exhibits sound therapeutic effects on osteosarcopenia (OS). However, EZF's therapeutic effects on skeletal muscles are rarely reported. This study explored the mechanism of EZF in skeletal muscle during OS by integrating energy metabolism and metabolomics.
METHODS: After an ovariectomized rat model was established for 4 weeks, the rats were subjected to a 12-week intervention of EZF and alendronate. The rats' body weight, gastrocnemius muscle mass, degree of myofiber fibrosis, and myofiber cross-sectional area (CSA) were measured to evaluate the pathological state of the gastrocnemius muscle. The mitochondrial membrane potential and reactive oxygen species (ROS) levels were detected to assess mitochondrial function. Then, energy metabolite analysis and metabolomics were performed on the gastrocnemius muscle.
RESULTS: Compared to the model group, EZH increased CSA by 5.58% and decreased myofiber fibrosis by 15.11%. Notably, compared to the model group, EZH exhibited a 52.66% increase in mitochondrial membrane potential and a 44.32% reduction in ROS levels. Starch and sucrose metabolism, insulin secretion, insulin resistance, and galactose metabolism were the most significantly affected pathways in energy metabolism. Thirty-five differential metabolites were found in the metabolomics of the gastrocnemius muscle, and EZF could effectively inhibit the sphingolipid metabolism pathway. Correlation analysis identified 13 differential metabolites that were significantly associated with skeletal muscle mass, ROS production, muscle fibrosis, and mitochondrial function, suggesting that these metabolites may play important roles in the progression of skeletal muscle lesions.
CONCLUSIONS: EZF alleviates OS by regulating skeletal muscle physiological indicators, mitochondrial function, and energy metabolism.

Keywords:  energy metabolism; metabolomics; muscle; osteosarcopenia; sarcopenia

DOI:  https://doi.org/10.1002/ame2.70241
Tissue Eng Part B Rev. 2026 Jun 27. 19373368261460337

Photobiomodulation Targets Mitochondrial Homeostasis for Diabetic Wound Healing.

Feng Lai, Yuxiu Mai, Zhaodan Wang, Chao Wang, Shulan Xu.

  Diabetes mellitus is a global public health problem, and impaired wound healing is a complication that significantly reduces patients' quality of life. Dysregulation of mitochondrial homeostasis is a key pathological feature contributing to impaired wound healing in diabetes. This dysregulation increases oxidative stress, resulting in impaired energy metabolism, endothelial dysfunction, and prolonged inflammatory responses. Photobiomodulation (PBM) is a noninvasive therapy that has been successfully used to promote diabetic wound healing by modulating mitochondrial homeostasis via multiple mechanisms. In this review, we have systematically summarized the following roles of PBM in restoring mitochondrial homeostasis to accelerate diabetic wound healing: improving mitochondrial dysfunction and oxidative stress through cytochrome C oxidase in the electron transport chain, thereby enhancing oxidative phosphorylation and adenosine triphosphate production; modifying mitochondrial dynamics by inhibiting the expression of dynamin-related protein 1 and promoting mitofusin-2 expression to restore mitochondrial morphology and function; reducing inflammation and promoting macrophage polarization from the M1 to M2 phenotype; activating signaling pathways (e.g., VEGF, PI3K/AKT/mTOR/GSK3-β, AMPK, RAS/MAPK, JAK/STAT, NF-κB, TGF-β/Smad) to enhance cell proliferation and angiogenesis and resolve inflammation. Beyond monotherapy, this review synthesizes the burgeoning field of PBM in combination with advanced therapeutic strategies, such as hydrogels, nanomaterials, small-molecule drugs, adipose-derived stem cells, and extracellular vesicles, highlighting their synergistic potential for enhanced efficacy. Finally, this review critically addresses the prevailing challenges in clinical translation, particularly the lack of standardized treatment parameters, and proposes future research directions. This comprehensive overview aims to solidify the scientific foundation of PBM and inspire the design of integrated, precision therapeutic strategies for diabetic wound management.

Keywords:  angiogenesis; diabetic wound healing; endothelial dysfunction; mitochondrial homeostasis; oxidative stress; photobiomodulation

DOI:  https://doi.org/10.1177/19373368261460337
Int J Mol Sci. 2026 Jun 21. pii: 5599. [Epub ahead of print]27(12):

Mitochondria: The Crossroads of Complement Activation and Kidney Injury Progression.

Madison K McGraw, Nirmala Parajuli.

  Acute kidney injury, a broad term associated with diverse etiologies, is a common pathological condition that develops into chronic disease via mechanisms that have yet to be fully understood. Key processes that promote chronic disease transition include mitochondrial dysfunction and aberrant complement system activation, specifically inducing inflammation and accumulation of pro-fibrotic changes. Although emerging evidence strongly indicates that these two processes are closely intertwined, identification of appropriate therapeutic targets remains limited. Among complement proteins, terminal portions of the cascade, including complement 5 (C5), exert particularly robust effects on mitochondrial function across tissues, including the kidney. Moreover, C5 is the most terminal portion of the cascade to produce a highly pro-inflammatory anaphylatoxin, positioning C5 as an ideal clinical target during kidney injury/disease. In this review, we will hence summarize current knowledge regarding mitochondrial contributions to kidney pathophysiology through the lens of the close relationship between mitochondria and the complement system, particularly C5.

Keywords:  C5; C5aR1; acute kidney injury; chronic kidney disease; complement system; kidney pathology; mitochondria

DOI:  https://doi.org/10.3390/ijms27125599